CYCLIC POLYPEPTIDES FOR THE TREATMENT OF HEART FAILURE

摘要

The invention provides a cyclic polypeptide of Formula I (SEQ ID NO: 1):;X1-R-X3-X4-L-S-X7-X8-X9-X10-X11-X12-X13  I;or an amide, an ester or a salt thereof, or a bioconjugate thereof, wherein X1, X3, X4, X7, X8, X9, X10, X11, X12 and X13 are defined herein. The polypeptides are agonist of the APJ receptor. The invention also relates to a method for manufacturing the polypeptides of the invention or bioconjugates thereof, and their therapeutic uses such as treatment or prevention of acute decompensated heart failure (ADHF), chronic heart failure, pulmonary hypertension, atrial fibrillation, Brugada syndrome, ventricular tachycardia, atherosclerosis, hypertension, restenosis, ischemic cardiovascular diseases, cardiomyopathy, cardiac fibrosis, arrhythmia, water retention, diabetes (including gestational diabetes), obesity, peripheral arterial disease, cerebrovascular accidents, transient ischemic attacks, traumatic brain injuries, amyotrophic lateral sclerosis, burn injuries (including sunburn) and preeclampsia. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

主权项

1. A method of treating or preventing a disease or disorder responsive to the agonism of the APJ receptor, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a cyclic polypeptide having the following formula I (SEQ ID NO: 1):
X1-R-X3-X4-L-S-X7-X8-X9-X10-X11-X12-X13  Iwherein:
X1 is the N-terminus of the polypeptide and is either absent, Q, A or pE or X1 is selected from C, c, hC, D-hC; wherein the side chain of C, c, hC or D-hC form a disulfide bond with the side chain of X7; X3 is P or X3 is selected from C, c, hC and D-hC; wherein the side chain of C, c, hC or D-hC forms a disulfide bond with the side chain of X7; X4 is R or X4 is selected from C, c, hC and D-hC; wherein the side chain of C, c, hC or D-hC forms a disulfide bond with the side chain of X7; wherein only one of X1, X3 and X4 is a sulfur contain amino-acid selected from C, c, hC and D-hC; X7 is C, c, hC or D-hC; and the side chain of X7 forms a disulfide bond with the side chain of C, c, hC or D-hC of either X1, X3 or X4; X8 is K or F; X9 is G, A, a or absent; X10 is P or absent; X11 is D-Nle, Nle, M or f; and X12 is absent or P, f, a, D-Nva or D-Abu; X13 is the C-terminus and is absent or is selected from (N-Me)F, F, f, a, y and Nal; wherein: Nle is L-norleucine; D-Nle is D-norleucine; D-hC is D-homocysteine hC is L-homocysteine; Nal is L-naphathaline; D-Nva is D-norvaline; D-Abu is D-2-aminobutyric acid; pE is L-pyroglutamic acid; or an amide, an ester or a salt of the polypeptide; or a polypeptide substantially equivalent
thereto.